rs61735534

Positions:

chr15-42359878-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_000070.3: c.73C>T variant in CAPN3 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 25 (p.His25Tyr). The filtering allele frequency of this variant is 0.02825 for African/African American exome chromosomes (the lower threshold of the 95% CI of 530/251040) in gnomAD v2.1.1, which is higher than the LGMD VCEP threshold (≥0.003) for BA1 and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.12, which is above the LGMD VCEP threshold predicting a benign impact on CAPN3 function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA7510845/MONDO:0015152/187

Frequency

Genomes: 𝑓 0.0081 ( 14 hom., cov: 32)

Exomes 𝑓: 0.00078 ( 22 hom. )

Consequence

CAPN3
NM_000070.3 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: 0.656

Variant links:

Genes affected

CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

CAPN3 links:

ENSG00000258461 (HGNC:):

ENSG00000258461 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3 linkuse as main transcript	c.73C>T	p.His25Tyr	missense_variant	1/24	ENST00000397163.8	NP_000061.1	P20807-1
CAPN3	NM_024344.2 linkuse as main transcript	c.73C>T	p.His25Tyr	missense_variant	1/23		NP_077320.1	P20807-3
CAPN3	NM_173087.2 linkuse as main transcript	c.73C>T	p.His25Tyr	missense_variant	1/21		NP_775110.1	P20807-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8 linkuse as main transcript	c.73C>T	p.His25Tyr	missense_variant	1/24	1	NM_000070.3	ENSP00000380349.3		P20807-1
ENSG00000258461	ENST00000495723.1 linkuse as main transcript	n.*105+5425C>T		intron_variant		2		ENSP00000492063.1		A0A1W2PQD3

Frequencies

GnomAD3 genomes

AF:

0.00805

AC:

1226

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0283

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00211

AC:

530

AN:

251040

Hom.:

AF XY:

0.00177

AC XY:

240

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.0305

Gnomad AMR exome

AF:

0.000954

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000775

AC:

1133

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000688

AC XY:

500

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0285

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00171

GnomAD4 genome

AF:

0.00806

AC:

1228

AN:

152342

Hom.:

Cov.:

AF XY:

0.00744

AC XY:

554

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.0282

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00319

Hom.:

Bravo

AF:

0.00980

ESP6500AA

AF:

0.0286

AC:

126

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00268

AC:

325

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 16, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal recessive limb-girdle muscular dystrophy type 2A

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Benign, reviewed by expert panel

curation

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Jan 07, 2025

The NM_000070.3: c.73C>T variant in CAPN3 is a missense variant predicted to cause substitution of histidine by tyrosine at amino acid 25 (p.His25Tyr). The filtering allele frequency of this variant is 0.02825 for African/African American exome chromosomes (the lower threshold of the 95% CI of 530/251040) in gnomAD v2.1.1, which is higher than the LGMD VCEP threshold (≥0.003) for BA1 and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.12, which is above the LGMD VCEP threshold predicting a benign impact on CAPN3 function (≤0.1; BP4 not met). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/07/2025): BA1. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.4

DANN

Benign

0.87

DEOGEN2

Benign

0.0036

T;.;.;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.89

D;D;D;D

MetaRNN

Benign

0.0031

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.55

.;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

0.18

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.19

T;T;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.13, 0.082

.;B;B;B

Vest4

0.17

MVP

0.76

MPC

0.19

ClinPred

0.010

GERP RS

4.0

Varity_R

0.041

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over